DJ-1 Mutations are Rare in a Swedish Parkinson Cohort

Mutations in the PARK7 gene, DJ-1, have been reported to cause early-onset and familial Parkinson’s disease (PD). The function of DJ-1 and how it contributes to the development of the disease is not clear today, but several studies report that DJ-1 is responsive to oxidative stress and important for the maintenance of mitochondria. We have screened three coding regions of DJ-1 (exon 2, 5 and 7) in a Swedish Parkinson cohort. The Swedish PD material consisted of 67 patients with a self reported positive family history of PD and 77 patients with early-onset of disease (≤50 years old). We detected two patients with the previously reported synonymous mutation, Ala167Ala (c.501A>G, rs71653621), in exon 7. No Ala167Ala carriers were identified among 213 neurologically healthy Swedish controls. Mechanisms by which the synonymous Ala167Ala mutation can have consequences are unknown. It may affect the mRNA stability, secondary structure of mRNA, synthesis, turnover, protein folding and function. We could show a 1.3% decrease in DJ-1 mRNA folding energy in the A<G substituted sequence compared to the wild type sequence in silico, suggesting a possible small effect of Ala167Ala on DJ-1 gene function. This is the first report on an identified DJ-1 mutation in Swedish PD patients. Our results, in combination with those of previous studies, strengthen the hypothesis that alterations in DJ-1 are not a common cause of familial and early-onset PD world-wide

Influence of ghrelin on the central serotonergic signaling system in mice

AbstractThe central ghrelin signaling system engages key pathways of importance for feeding control, recently shown to include those engaged in anxiety-like behavior in rodents. Here we sought to determine whether ghrelin impacts on the central serotonin system, which has an important role in anxiety. We focused on two brain areas, the amygdala (of importance for the mediation of fear and anxiety) and the dorsal raphe (i.e. the site of origin of major afferent serotonin pathways, including those that project to the amygdala). In these brain areas, we measured serotonergic turnover (using HPLC) and the mRNA expression of a number of serotonin-related genes (using real-time PCR). We found that acute central administration of ghrelin to mice increased the serotonergic turnover in the amygdala. It also increased the mRNA expression of a number of serotonin receptors, both in the amygdala and in the dorsal raphe. Studies in ghrelin receptor (GHS-R1A) knock-out mice showed a decreased mRNA expression of serotonergic receptors in both the amygdala and the dorsal raphe, relative to their wild-type littermates. We conclude that the central serotonin system is a target for ghrelin, providing a candidate neurochemical substrate of importance for ghrelin's effects on mood

Possible Involvement of a Mitochondrial Translation Initiation Factor 3 Variant Causing Decreased mRNA Levels in Parkinson's Disease

Genes important for mitochondrial function have been implicated in Parkinson's disease (PD). Mitochondrial translation initiation factor 3 (MTIF3) is a nuclear encoded protein required for the initiation of complex formation on mitochondrial ribosomes. Dysfunction of MTIF3 may impair mitochondrial function and dopamine neurons appear to be particularly vulnerable to oxidative stress, which may relate to their degeneration in PD. An association was recently reported between the synonymous rs7669(C>T) in MTIF3 and PD in a German case-control material. We investigated rs7669 in a Swedish Parkinson case-control material. The study revealed no significant association of the individual genotypes or alleles with PD. When comparing the combined TT/CT-genotypes versus the CC-genotype, we observed a significant association (P = .0473) with PD. We also demonstrated that the TT-genotype causes a significant decrease in MTIF3 mRNA expression compared to the CC-genotype (P = .0163). Our findings support the hypothesis that MTIF3 may be involved in the etiology of PD

Glucagon-Like Peptide-1 and its Analogues Act in the Dorsal Raphe and Modulate Central Serotonin to Reduce Appetite and Body Weight.

Glucagon-like peptide-1 (GLP-1) and serotonin play critical roles in energy balance regulation. Both systems are exploited clinically as anti-obesity strategies. Surprisingly whether they interact in order to regulate energy balance is poorly understood. Here we investigated mechanisms by which GLP-1 and serotonin interact at the level of the CNS. Serotonin depletion impaired the ability of exendin-4, a clinically utilized GLP-1 analogue, to reduce body weight in rats, suggesting serotonin is a critical mediator of the energy balance impact of GLP-1R activation. Serotonin turnover and expression of 5HT2A and 5HT2C serotonin receptors in the hypothalamus were altered by GLP-1R activation. We demonstrate that 5HT2A, but surprisingly not 5HT2C, receptor is critical for weight-loss, anorexia and fat mass reduction induced by central GLP-1R activation. Importantly, central 5HT2A receptors are also required for peripherally injected liraglutide to reduce feeding and weight. Dorsal raphe (DR) harbors cell bodies of serotonin producing neurons that supply serotonin to the hypothalamic nuclei. We show that GLP-1R stimulation in DR is sufficient to induce hypophagia and increase electrical activity of the DR serotonin neurons. Finally our results disassociate brain metabolic and emotionality pathways impacted by GLP-1R activation. This study identifies serotonin as new critical neural substrate for GLP-1 impact on energy homeostasis, and expands the current map of brain areas impacted by GLP-1R activation.This research was funded by the Swedish Research Council (2014-2945 and 2013-7107), Novo Nordisk Foundation Excellence project grant, Ragnar Söderberg Foundation, Harald Jeanssons Stiftelse and Greta Jeanssons Stiftelse, and Magnus Bergvalls Stiftelse

Dichotomy of Tyrosine Hydroxylase and Dopamine Regulation between Somatodendritic and Terminal Field Areas of Nigrostriatal and Mesoaccumbens Pathways

Measures of dopamine-regulating proteins in somatodendritic regions are often used only as static indicators of neuron viability, overlooking the possible impact of somatodendritic dopamine (DA) signaling on behavior and the potential autonomy of DA regulation between somatodendritic and terminal field compartments. DA reuptake capacity is less in somatodendritic regions, possibly placing a greater burden on de novo DA biosynthesis within this compartment to maintain DA signaling. Therefore, regulation of tyrosine hydroxylase (TH) activity may be particularly critical for somatodendritic DA signaling. Phosphorylation of TH at ser31 or ser40 can increase activity, but their impact on L-DOPA biosynthesis in vivo is unknown. Thus, determining their relationship with L-DOPA tissue content could reveal a mechanism by which DA signaling is normally maintained. In Brown-Norway Fischer 344 F1 hybrid rats, we quantified TH phosphorylation versus L-DOPA accumulation. After inhibition of aromatic acid decarboxylase, L-DOPA tissue content per recovered TH protein was greatest in NAc, matched by differences in ser31, but not ser40, phosphorylation. The L-DOPA per catecholamine and DA turnover ratios were significantly greater in SN and VTA, suggesting greater reliance on de novo DA biosynthesis therein. These compartmental differences reflected an overall autonomy of DA regulation, as seen by decreased DA content in SN and VTA, but not in striatum or NAc, following short-term DA biosynthesis inhibition from local infusion of the TH inhibitor α-methyl-p-tyrosine, as well as in the long-term process of aging. Such data suggest ser31 phosphorylation plays a significant role in regulating TH activity in vivo, particularly in somatodendritic regions, which may have a greater reliance on de novo DA biosynthesis. Thus, to the extent that somatodendritic DA release affects behavior, TH regulation in the midbrain may be critical for DA bioavailability to influence behavior

Noisy galvanic vestibular stimulation promotes GABA release in the substantia nigra and improves locomotion in hemiparkinsonian rats

Dopamine related disorders usually respond to dopaminergic drugs, but not all symptoms are equally responsive. In Parkinson’s disease (PD) in particular, axial symptoms resulting in impaired gait and postural control are difficult to treat. Stochastic vestibular stimulation (SVS) has been put forward as a method to improve CNS function in dopamine related disorders, but the mechanisms of action are not well understood. This thesis aimed to investigate the effects of SVS on neuronal brain activity and to evaluate the possible enhancing effect of SVS on motor control in PD and on cognitive functions and motor learning in Attention deficit hyperactivity disorder (ADHD). Behavioural tests were conducted in the 6-OHDA rat model of PD using the accelerating Rotarod and the Montoya skilled reach test to evaluate the effect of SVS on motor control. The effect of SVS on brain activity was assessed using in vivo microdialysis and immunohistochemistry. We evaluated the effect of SVS on postural control and Parkinsonism in patients with PD and the effect of SVS on cognitive function in people with ADHD. The behavioural animal studies indicate that SVS may have an enhancing effect on locomotion, but not skilled forepaw function. SVS increased GABA transmission in the ipsilesional substantia nigra (SN) and may have a rebalancing effect on dysfunctional brain activity. SVS increased c-Fos activity more than levodopa and saline in the vestibular nucleus of all animals. c-Fos expression was also higher in this region in the 6-OHDA lesioned than in shamlesioned animals, supporting the theory that SVS may have larger effects in the dopamine depleted brain. SVS increased c-Fos expression in the habenula nucleus substantially more than levodopa did. Furthermore, SVS and levodopa had similar effects on many brain regions, including the striatum, where saline had no effect. The clinical studies revealed improvement of postural control in PD during SVS. There was a trend towards reduced Parkinsonism during SVS when off levodopa. No substantial effects were found on cognitive performance in ADHD. In PD, SVS may improve motor control by inhibiting the overactive SN, possibly through a non-dopaminergic modulatory pathway involving increased neurotransmission in the habenula nucleus. SVS could be trialled in larger studies to evaluate long-term effects on treatment resistant axial symptoms associated with PD

To lead by good example : Factors that influence the nurses’ function to lead

Ett av sjuksköterskans kompetensområden är ledarskap. Han/hon ska strukturera omvårdnadsarbetet så att det ges en så god omvårdnad som möjligt till patienten. Ledningsfunktionen påverkas av olika faktorer som kan ge inverkan på omvårdnaden. Syftet med litteraturstudien var att belysa faktorer som påverkar sjuksköterskans ledningsfunktion. Studien utfördes som en litteraturstudie. Resultatet visade att sjuksköterskans ledningsfunktion ofta inte synliggörs i organisationen och bland vårdpersonal och att det finns en brist på förståelse för hans/hennes uppgift som ledare. Det var även svårt för sjuksköterskan att förstå sin egen funktion som ledare då han/hon hade svårt att koppla den till sin kompetens. Utbildning inom ledarskap sågs som en brist men utbildning var en viktig faktor för att utveckla kompetensen som ledare. För att kunna utföra och utveckla sin roll som ledare behöver den närmsta chefen ge sjuksköterskan autonomi och feedback för hans/hennes prestation. Sammanfattningsvis bör mer utbildning om ledarskap införas för sjuksköterskan och det bör även utforskas mer om ämnet. Bristen på feedback är synlig på arbetsplatsen och bör därför införas i praktiskt vårdverksamhet till exempel att det varje dag är obligatoriskt att gruppen diskuterar dagen som har gått. Detta för att öka kunskaperna om ledarskap vilket i sin tur leder till att sjuksköterskans roll som ledare blir mer synlig.One of the nurses’ areas of expertise is leadership. He/she will organize nursing care in order to provide as good care as possible for the patient. The lead function is affected by various factors that can influence the care. The purpose of this study was to focus on factors that influence nurses le role. The study was conducted as a literature review. The results showed that nurses function to lead is often not made visible in the organization and among health professionals and that there is a lack of understanding of his/her role as a leader. It was also difficult for nurses to understand their function as a leader when he/she found it difficult to connect it to their skills. Education in leadership was seen as a shortage but education was an important factor to develop leader skills. To perform and develop their role as a leader they need the nearest superior head to give the nurses autonomy and feedback on his/her performance. In conclusion, more education about leadership needs to be introduced to the nurse and it should also be explored more about the subject. The lack of feedback is visible in the workplace and should therefore be included in practical healthcare, for example obligatory group discussions about the day’s work every day. This is to increase knowledge about leadership, which in turn leads to the nurses’ role as a leader to become more visible

Den icke-handlande industrins förutsättningar att bli fossilfria innan år 2030

Den 1 januari 2018 träder Sveriges klimatlag i kraft. Den innebär bland annat nyaoch långsiktiga mål för de klimatpåverkande utsläppen. De utsläpp som inteomfattas av EU:s handelssystem för utsläppsrätter ska ha minskat med 63 procent2030 jämfört med 1990 och med 75 procent 2040.Den här undersökningen är framtagen som ett underlag för Naturvårdsverketsarbete med att begränsa utsläppen av växthusgaser i Sverige. Rapporten redovisar slutsatser från intervjuer med företrädare från några industriföretag angående deras förutsättningar att bli fossilbränslefria för år 2030.